Bleeding disorders and postpartum hemorrhage by mode of delivery: a retrospective cohort study

Background Pregnant persons with bleeding disorders and their potentially affected newborns are at a higher risk of peripartum bleeding complications. The safest mode of delivery for persons with bleeding disorders remains debated, leading to uncertainties in decision-making between the patient and her multidisciplinary team. Objectives This study aimed to describe maternal outcomes for pregnant persons with bleeding disorders by mode of delivery and to examine whether postpartum hemorrhage (PPH) and neonatal hemorrhagic manifestations are associated with the mode of delivery. Methods We collected retrospective data on pregnant persons with bleeding disorders who delivered at a single center from 2010 to 2021. Descriptive statistics, Fisher exact test, and odds ratios were used for analysis. Results A total of 82 pregnancies in 56 subjects were included. Hemophilia A and von Willebrand disease represented the largest cohort, at 30% (17/56) each. Overall rates of primary and secondary PPH were 7.3% (6/82) and 17.4% (12/69), respectively. We did not find a statistically significant difference between mode of delivery and PPH. Upon comparing vaginal and cesarian deliveries, we found an odds ratio of 0.7 (95% CI, 0.1-3.4) for primary PPH and 2.6 (95% CI, 0.4-16.4) for secondary PPH. One male newborn with severe hemophilia A was treated for a suspected intracranial hemorrhage. Conclusion In our cohort, high rates of PPH remained an important complication for pregnant persons with bleeding disorders. There was no significant difference in PPH based on modes of delivery. The small sample size likely limited the power of our study, and consequently, future larger studies are needed.


| I N T R O D U C T I O N
Pregnant persons with bleeding disorders and their potentially affected newborns are at higher risk of peripartum bleeding complications compared to the general population [1,2]. The safest mode of delivery for pregnant persons with bleeding disorders remains debated and primarily driven by obstetrical indications [3,4]. While planned cesarian delivery (CD) in persons without bleeding disorders may offer a lower overall incidence of postpartum hemorrhage (PPH) [5] and less short-term adverse outcomes than vaginal deliveries, the risk of bleeding increases with repeated CDs due to higher risk of placental abnormalities and surgical complexities [6]. Spontaneous vaginal delivery (SVD) offers the least invasive approach and decreases the need for CD in subsequent deliveries [3,[7][8][9], but it may complicate laboratory monitoring and factor concentrate administration essential for safe deliveries in persons with bleeding disorders.
Induction of labor (IOL) involves using planned techniques to stimulate uterine contractions and achieve delivery, which may include cervical ripening, oxytocin, or amniotomy. Compared to planned CD, IOL can provide similar predictability while minimizing the risks of bleeding and associated morbidity [7][8][9]. However, IOL was shown to increase the risk of peripartum bleeding events in pregnant persons on anticoagulation [10].
Managing pregnant persons with bleeding disorders is challenging due to insufficient evidence to guide complex decision-making. There are debates among experts on whether to choose CD or vaginal delivery without instrumentation and prolonged labor [3,4]. This results in clinical uncertainties and variable practices that affect shared decision-making, preparedness, and clinical outcomes. Randomized controlled trials are unlikely due to the rarity of bleeding disorders [11]; thus, observational studies are crucial to inform practice and areas for further research. This study aimed to describe the association between mode of delivery and maternal and neonatal outcomes, specifically PPH and neonatal intracranial hemorrhage, in pregnant persons with bleeding disorders.

| M E T H O D S
We conducted a retrospective cohort study of pregnant persons with bleeding disorders managed at the Ottawa Regional Bleeding Disorders program at The Ottawa Hospital (TOH). The Ottawa Health Science Network Research Ethics Board approved all study procedures (ID: 20210313-01H).
The study included subjects who met 2 criteria: 1) a known bleeding disorder diagnosis, including hemophilia A or B, von Willebrand disease (VWD), rare bleeding disorders, or inherited platelet function defects, and 2) delivered at TOH between January 1, 2010, and July 15, 2021 (further details in Supplementary Material 1).
Persons with bleeding disorders not otherwise specified or with bleeding of an unknown cause were excluded. Data were collected on maternal age and gestational age at delivery, type of bleeding disorder and its characteristics, mode of delivery, and peripartum hemostatic management. Each delivery was recorded as a separate event. Maternal outcomes were recorded, including primary and secondary PPH, as defined by the American College of Obstetrics and Gynecology [12]. Primary PPH was blood loss ≥1000 mL with signs and symptoms of hypovolemia within 24 hours of delivery regardless of the route of delivery or blood loss >500 mL in a vaginal delivery. Secondary PPH was any abnormal or excessive vaginal bleeding beyond 24 hours and up to 12 weeks postpartum, as documented in clinical notes. Other recorded outcomes included maternal death, morbidity, length of hospital stay, and number of packed red blood cell (PRBC) or platelet transfusions, when applicable. Neonatal outcomes were also collected, including neonatal death, morbidity, length of hospital stay, and transfer to a pediatric hospital or the neonatal intensive care unit.
Descriptive statistics were used to summarize the baseline characteristics of the cohort. Missing values were not omitted from the data analysis. Fisher exact test was used to examine the significance of the association between the mode of delivery and PPH. Odds ratios (ORs) were used to analyze the associations between PPH and vaginal or cesarian deliveries and between PPH and planned or unplanned deliveries.

| R E S U L T S A N D D I S C U S S I O N
Eighty-two deliveries in 56 persons with bleeding disorders had care at TOH during the study period. The mean (±SD) maternal age was 31.4 (±4.5) years. The mean (±SD) gestational age was 38.6 (±3.0) weeks. Hemophilia A and VWD type 1 were the most common diagnoses, with each representing 30.4% (17/56) of the cohort ( Table 1).
All subjects had pre-established diagnoses, except 3 who were diagnosed following their first pregnancy (2 VWD type 1 and 1 factor [F] XIII deficiency). SVD was the most common mode of delivery (43.9%), followed by IOL with intended vaginal delivery (29.3%), planned CD (17.0%), and emergent CD (9.8%) ( Table 1). In the latter group, 2 subjects failed IOL and required emergent CD.

Essentials
• Peripartum management of persons with bleeding disorders requires additional research efforts.
• We described maternal and neonatal outcomes from a single Canadian tertiary care center.
• Persons with bleeding disorders had high rates of secondary postpartum hemorrhage.
• We found no significant difference between rates of postpartum hemorrhage and mode of delivery.  (Table 3). Upon comparing unplanned (SVD and emergent CD) to planned (IOL and planned CD) deliveries, the OR was 0.5 (95% CI, 0.1-2.3) for primary PPH and 1.1 (95% CI, 0.3-3.7) for secondary PPH (Table 3). Table 4 describes each PPH event, including the type of bleeding disorder, coagulation profile, mode of delivery, and peripartum hemostatic therapies.
One patient with VWD type 2A received 2 units of PRBCs (P6, PPH rates were numerically lower with CDs and highest with IOL, but no statistically significant differences were found compared to vaginal deliveries. Recent observational studies in the general population have also shown lower rates of PPH with CDs [5,6,13]. However, Wolf et al. [14] observed a higher frequency of primary PPH for persons with bleeding disorders who had an elective or emergent CD, but secondary PPH was only noted with vaginal deliveries. An Australian observational study of 23 deliveries in subjects with VWD found primary PPH in 44% of their cohort and more frequently with CD, but the differences were not statistically significant [15]. Both studies used the World Health Organization definition of primary PPH (blood loss >500 mL in the first 24 hours) and secondary PPH (abnormal bleeding between 24 hours and up to 6 weeks postpartum), which may have contributed to the differences in findings. Planned CD for this patient population may have an advantage due to its predictability in scheduling the procedure and allowing for appropriate care coordination and availability of laboratory, medications, and expert care, which fits with international surgical standards for T A B L E 1 Baseline characteristics of the patients.

Characteristics
No. (%)  [20,[23][24][25][26]. Therefore, higher target of factor levels may be needed in the peripartum and postpartum periods as factor levels also rise physiologically in persons without bleeding disorders. However, the optimal target levels remain elusive, and current approaches may not be optimal. Further studies are needed to guide practice changes in peripartum prophylaxis in subjects with VWD and hemophilia A. Observing fewer secondary PPH in subjects who received hemostatic therapies is a notable finding; however, the heterogeneity of bleeding disorders and treatment regimens limits its generalizability.
Given the high rates of secondary PPH observed in our cohort, it may be imperative to consider the use of antifibrinolytic agents postpartum, regardless of factor levels. TXA is a safe, well-tolerated, costeffective [27], and clinically effective option for preventing PPH without risks of thrombosis [28,29].
Our study has limitations. The statistical power was limited due to a small sample size in a single center and the use of estimated blood loss and clinical documentation to assess PPH. The lack of complete data on secondary PPH also limits its accuracy. Additionally, the lack of available information on race and ethnicity impedes identifying potential health disparities. Furthermore, the absence of standardized In summary, we found high rates of primary and secondary PPH in pregnant persons with bleeding disorders, which was not influenced significantly by delivery modes. The rate of secondary PPH was higher than anticipated at 17.4%, which is concerning as it is often diagnosed after discharge. High alert is needed to avoid delaying treatments, and extended antifibrinolytic therapy may be considered. Primary PPH still occurred in subjects with hemophilia A and VWD despite factor levels exceeding the recommended threshold of 0.50 IU/mL, which raised questions about optimal factor level targets. Larger multicenter studies are needed to confirm these findings.

ACKNOWLEDGMENTS
We thank Arash Shamloo, PhD, for his contribution to the statistical analysis. We also thank Iris Perelman, MSc, for identifying the patient cohort using the Ottawa Hospital data warehouse.

FUNDING
The study did not receive any funding.

AUTHOR CONTRIBUTIONS
All authors designed the study. B.N. and R.K. collected the data and performed the data analysis with the help of a statistician. All authors reviewed the data in aggregates, discussed the results, and contributed to the analytical interpretation and the final manuscript. All authors read and approved the final version of the paper.

RELATIONSHIP DISCLOSURE
There are no competing interests to disclose.